Drosophila melanogaster
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1007640 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25725826_1.fastq.gz | Fastqsanger.gz | |||
| SRR25725826_2.fastq.gz | Fastqsanger.gz | |||
| SRR25724582.fastq.gz | Fastqsanger.gz | |||
| SRR25724583.fastq.gz | Fastqsanger.gz | |||
| SRR25724584.fastq.gz | Fastqsanger.gz |
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Project description:Target-directed miRNA degradation (TDMD) is a process of post-transcriptional regulation of miRNA stability in animals induced by an extended pairing of Ago-bound miRNAs with specialized complementary RNA targets. As suggested by studies on human cell culture, Ago engaged with the extended duplex is recognized by the ZSWIM8 receptor of the Cullin-RING-ligase complex (CRL3), which also contains Cul3, EloB, and EloC proteins. The CRL activity is accelerated by the neddylation of Cul3 with the involvement of the E2 conjugating protein UbcE2M. The CRL ubiquitinates Ago, resulting in proteolysis of Ago and degradation of the released miRNAs. To date, the molecular mechanism of TDMD has not been studied in other species. To further characterize TDMD in animals, we investigated the protein Dora, the Drosophila ortholog of ZSWIM8, in the culture of Drosophila ovarian somatic cells (OSC). We showed that Dora in OSCs localizes in protein granules unrelated to P- and GW-bodies. The dora knockout resulted in the accumulation of multiple miRNAs, including miR-7-5p, and transcriptome-wide affected the mRNA targets of differentially expressed miRNAs. We also showed that Dora associates with proteins of the CRL3 complex, and the depletion of CRL3 components or inhibition of Cul3 neddylation upregulates miR-7-5p. We concluded that the molecular mechanism of TDMD is conserved in humans and Drosophila. Finally, we found that cells without Dora have an impaired Notch signaling pathway, indicating that TDMD in OSCs may contribute to the modulation of the Notch pathway.
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Project description:MicroRNAs (miRNAs) associate with Argonaute (AGO) proteins to direct widespread post-transcriptional gene repression. Although association with AGO typically protects miRNAs from nucleases, extensive pairing to some unusual target RNAs can trigger miRNA degradation. Here we found that this target-directed miRNA degradation (TDMD) required the ZSWIM8 Cullin-RING E3 ubiquitin ligase. This and other findings suggested and supported a mechanistic model of TDMD in which target-directed proteolysis of AGO by the ubiquitin–proteasome pathway exposes the miRNA for degradation. Moreover, loss-of-function studies indicated that the ZSWIM8 Cullin-RING ligase accelerates degradation of numerous miRNAs in cells of mammals, flies, and nematodes, thereby specifying the half-lives of most short-lived miRNAs. These results elucidate the mechanism of TDMD and expand the inferred role of TDMD in shaping miRNA levels in bilaterian animals.
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